Differential regulation of human α1-adrenoceptor subtypes

Abstract

We have compared the agonist-induced down-regulation of human alpha1A-, alpha1B- and alpha1D-adrenoceptors upon stable expression in rat-1 fibroblasts. During a 24-h incubation the agonist phenylephrine downregulated alpha1A- and alpha1 -adrenoceptors in a concentration-dependent manner. While maximum downregulation was similar for both subtypes, the threshold concentration for significant reductions was markedly higher for alpha1A- than for alpha(1B-adrenoceptors (10 microM vs. 100 nM). The downregulation of both subtypes by 100 microM phenylephrine was time-dependent, and significant reductions were observed already after 2-4 h. In contrast, incubation of alpha1D-adrenoceptor-expressing cells with phenylephrine increased receptor number in a time- and concentration-dependent manner. The downregulation of alpha1B-adrenoceptors by 100 microM phenylephrine for 24 h was accompanied by a matching reduction in mRNA abundance, but no such reduction was seen for alpha-adrenoceptors. These treatment conditions also caused a functional desensitization of agonist-stimulated inositol phosphate formation for alpha1A- and alpha1B- but not for alpha1D-adrenoceptors. Treatment with the phorbol ester phorbol-12-myristate-13-acetate did not change receptor density or mRNA abundance and did not cause functional desensitization. We conclude that human alpha1-adrenoceptor subtypes are differentially regulated by agonist treatment even if they are expressed in the same cell line.

Cellular Trafficking of Human α1a-Adrenergic Receptors Is Continuous and Primarily Agonist-Independent

“…Although the phosphorylation sites and/or sequence elements used in agonist-induced internalization of ␣ 1a ARs remain to be identified, they are not found within the intracellular carboxy terminus of the receptor, because the elimination of this region does not prevent internalization or, for that matter, desensitization of the receptor (Price et al, 2002). Although our data strongly suggest that the ␣ 1a AR is not subject to agonist-induced degradation or trafficking to lysosomes, it has been reported that the ␣ 1a AR is down-regulated 60% after 6 h (Wise et al, 1995) or 30% after 3 h (Yang et al, 1999) of phosphatidylethanolamine exposure. The reason for these discrepancies remains unclear, but it is worth noting that the later report found no decrease in ␣ 1a AR levels from 3 to 24 h.…”

Stress Impairs α1A Adrenoceptor-Mediated Noradrenergic Facilitation of GABAergic Transmission in the Basolateral Amygdala

“…In other brain regions, repeated stress reduces mRNA levels of a 1 adrenoceptors (Miyahara et al, 1999). Adrenergic receptors desensitize or undergo downregulation following prolonged exposure to the agonist (Yang et al, 1999;Chalothorn et al, 2002). Thus, during stress exposure, excessive release of NE in the amygdala (Galvez et al, 1996;Quirarte et al, 1998;Tanaka et al, 2000) may be responsible for the impairment of the a 1A adrenoreceptor function.…”

Neuroplasticity and Calcium Signaling in Stressed Rat Amygdala

“…In other brain regions, repeated stress reduces mRNA levels of oci adrenoceptors (Miyahara et al, 1999). Adrenergic receptors desensitize or undergo downregulation following prolonged exposure to the agonist (Yang et al, 1999;Chalothom et al, 2002). Thus, during stress exposure, excessive release of NE in the amygdala (Galvez et al, 1996;Quirarte et al, 1998;Tanaka et al, 2000) may be responsible for the impairment of the aiA adrenoreceptor function.…”